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A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir

Cancer Gene Therapy volume 8, pages 890–896 (2001)Cite this article

Abstract

The c- erbB-2 gene is frequently overexpressed in human breast cancers as a result of gene amplification and/or elevated transcription. We therefore examined a possible usage of promoter regions of the c- erbB-2 gene to express a suicide gene preferentially in breast cancer cells. Previous studies did not reveal the minimal promoter region that enabled transcriptional activation specific to breast cancer cells. The present reporter gene assays using deletion mutants of the c-erbB-2 promoter region demonstrated that the 251-bp (−213/+38 from the transcriptional start site), but not the 125-bp, fragment (−87/+38) could direct transcription of the linked luciferase gene better than the SV40 immediate early promoter in breast cancer cells. In contrast, the 251-bp fragment-mediated promoter activity in nonbreast cancer cells and in normal fibroblasts was lower than the activity by the SV40 promoter. The 126-bp fragment (−213/−87) thereby contains a cis -acting element(s), which is responsible for the preferential transcriptional activity in breast cancer cells. An electrophoretic mobility shift assay suggested that a possible modification of a transcriptional factor was involved in the tumor specificity. Transfection with the plasmid DNA containing the herpes simplex virus thymidine kinase gene linked with the 251-bp promoter (p256-TK) resulted in increased sensitivity to ganciclovir in breast cancer, but not in nonbreast cancer cells. Administration of ganciclovir into nude mice bearing human breast tumors that were transfected with the p256-TK DNA suppressed subsequent growth of the transplanted tumors. These results suggest that delivery of a suicide gene linked with the 251-bp c-erbB-2 promoter can be a feasible therapeutic strategy specific to breast cancer. Cancer Gene Therapy (2001) 8, 890–896

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Acknowledgements

This work was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science and a grant-in-aid for scientific research on priority areas from the Minister of Education, Culture, Sports, Science, and Technology of Japan. We thank F. Hoffman-La Roche (Basel, Switzerland) for their generous gift of GCV.

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Authors and Affiliations

  1. Division of Pathology, Chiba, Japan

    Tomoko Maeda, Jiyang O-Wang & Masatoshi Tagawa

  2. Chiba Cancer Center Research Institute, Chiba, Japan

    Shigeru Sakiyama

  3. Department of Surgery II, School of Medicine, Chiba University, Chiba, Japan

    Tomoko Maeda, Hisahiro Matsubara, Takehide Asano & Takenori Ochiai

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  1. Tomoko Maeda
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  2. Jiyang O-Wang
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  7. Masatoshi Tagawa
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Correspondence to Masatoshi Tagawa.

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Maeda, T., O-Wang, J., Matsubara, H. et al. A minimum c-erbB-2 promoter-mediated expression of herpes simplex virus thymidine kinase gene confers selective cytotoxicity of human breast cancer cells to ganciclovir. Cancer Gene Ther 8, 890–896 (2001). https://doi.org/10.1038/sj.cgt.7700389

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